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A gene associated with an inherited form of Parkinson 's disease makes a protein that also affects the severity of Crohn's disease, according to study published in the October 9 issue of Nature Immunology. Although scientists have long suspected that this protein, leucine-rich repeat kinase 2 (LRRK2), plays a role in Crohn's, this study is the first to demonstrate how the protein regulates the disease. This knowledge could lead to new therapeutic strategies for the disorder.

Background

Crohn's disease is one of the most common forms of inflammatory bowel disease (IBD), an autoimmune condition that causes chronic, recurring inflammation in the gastrointestinal (GI) tract. In people with IBD, the immune system mounts an attack against the body's cells, which can lead to diarrhea, abdominal pain, and fatigue. In the worst cases, the immune cells create holes in the digestive tract, necessitating surgery.

The Centers for Disease Control and Prevention estimates that each year in the United States IBDs account for more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients. There is no cure for these debilitating conditions, which often appear when a person is between 15 and 30 years of age.

By screening the human genome, investigators have identified over 40 different genes associated with susceptibility to developing Crohn's disease, but it is still unknown how the proteins made by these genes are involved in the condition. One of these susceptibility genes makes LRRK2 protein. Exactly how it could contribute to IBD has been unclear.

Results of Study

NIH investigators led by Michael Lenardo, M.D., chief of the Molecular Development of the Immune System Section in NIAID's Laboratory of Immunology, examined the function of LRRK2 using a mouse model of IBD. The condition is induced in mice by adding dextran sulfate sodium (DSS) into the animals' drinking water. The team observed that mice that did not make LRRK2 developed more severe disease symptoms than normal mice after treatment with a 3-percent solution of DSS for 8 days.

To determine how LRRK2 could be involved in Crohn's disease, Zhizhu Liu, Ph.D., a member of Dr. Lenardo's team, searched a database of fruit fly genes. In fruit flies, LRRK2 is associated with a type of protein that binds to DNA and turns on specific genes. This protein, called nuclear factor of activated T cells 1 (NFAT1), regulates the function of immune system cells, including macrophages, dendritic cells, and T cells.

The team explored the possibility that LRRK2 also may be associated with NFAT1 in mammalian cells. In laboratory experiments, they observed that LRRK2 inhibited the activity of NFAT1 in mouse and human cells. Animal studies of IBD revealed that mice without LRRK2 had increased NFAT1 and macrophage activity, compared to normal mice.

To determine if these observations in animal and lab experiments also applied to people with IBD, the team examined immune cells isolated from four patients who had a mutation in the gene for LRRK2, and compared these cells to immune cells isolated from healthy volunteers. The patients made an alternate form of LRRK2 protein that degraded much more rapidly than protein from the healthy volunteers. NFAT1 activity also was higher in the patients' cells, compared to the healthy volunteers' cells.

Significance

The study findings indicate that reduced levels of LRRK2 may contribute to increased activity of NFAT1. Abnormal NFAT1 activity has been observed in the colon tissue of people with Crohn's disease and may contribute to disease severity. Although the link between Crohn's and Parkinson's disease is still unclear, the results from this study add to the current understanding of how LRRK2 regulates disease.

Additionally, this work demonstrates how using tools such as the fruit fly database and screening the human genome for markers of disease can be translated into findings in the lab that could greatly impact human health.

Next Steps

The team's observations suggest that enhancing the activity of LRRK2, as well as using drugs that can block NFAT1, may be a therapeutic strategy for treating Crohn's disease.